Drugs serve as positive reinforcers to maintain and strengthen behavior leading to their administration and can control behavior through their ability to function as discriminative stimuli. In many situations, drugs of abuse function through pharmacological and behavioral mechanisms to persistently sustain long sequences of drug seeking behavior that are very resistant to extinction. These long sequences of drug-seeking behavior can be analyzed using schedule-controlled behavior in the same way as operant behavior maintained by other events such as food or shock. Using a variety of self-administration procedures in rats and primates, ongoing experiments are being conducted to evaluate behavior maintained by drugs and the ability of pharmacological treatments, and/or behavioral manipulations to modify drug self-administration behavior and/or food-maintained behavior. These studies will compare responding maintained under fixed-ratio, fixed interval and complex second order schedules, by various drugs including cocaine, nicotine, benzodiazepines, morphine and other opioids. For example, since recent studies suggest a serotonergic mechanism underlying psychomotor stimulant action, an ongoing study is assessing the effects of sertraline, a selective serotonergic uptake inhibitor/antidepressant, on the reinforcing effects of i.v. nicotine in squirrel monkeys. In addition to differences in pharmacological efficacy of drugs to control or modify behavior, it is clear that behavioral and environmental factors play an important role in the control that even highly efficacious drugs exert on behavior. The focus of experiments in the newly established rhesus self-administration lab are to study the pharmacological, behavioral, and environmental variables involved in initiating and maintaining drug self-administration. since the ability of psychoactive drugs to maintain self-injection behavior will be modified by a number of environmental and behavioral factors, additional studies will be initiated to evaluate the development of tolerance to the reinforcing effects of psychoactive drugs and how the development of tolerance can be attenuated by environmental conditions.